NK-1 receptor antagonists for the treatment of cancer

ABSTRACT

The present invention relates to the use of certain NK-1 receptor antagonists, as, for example, substance P receptor antagonists, to treat cancer patients, particularly cancer patients afflicted with a small cell lung carcinoma, neuroendocrine tumor or extrapulmonary small cell carcinoma.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/786,128 filed Jan. 17, 1997, now U.S. Pat. No. 5,990,125 which is acontinuation of Provisional Application No. 60/010,232 filed Jan. 19,1996.

The present invention relates to the use of certain NK-1 receptorantagonists, (including certain substance P receptor antagonists) totreat cancer patients afflicted with a small cell lung carcinoma,APUDoma, astrocytoma, neuroendocrine tumor or extrapulmonary small cellcarcinoma.

Antal Orosz, et al., International Journal of Cancer, 1995, 60, 82-87,describe the use of a variety of peptidic substance P antagonists toinhibit the proliferation of small cell lung carcinoma, e.g., in thecell line designated NCl-H69). Paul Bunn et al., Cancer Research, 1994,54, 3602-3610, describe another series of substance P antagonists whichare also peptidic and which are capable of inhibiting in vitro growth ofa number of small cell lung carcinoma cell lines (e.g., those designatedNCl-H510, NCl-H345 and SHP-77).

SUMMARY OF THE INVENTION

The present invention relates to a method of treating cancer in amammal, including a human, comprising administering to such mammal atherapeutically effective amount of an NK-1 receptor antagonist selectedfrom the compounds described below.

“Treating cancer”, as used herein, means inhibiting or controlling theproliferation of a small cell lung carcinoma, APUDoma, neuroendocrinetumor, extrapulmonary small cell carcinoma or astrocytoma.

A “therapeutically effective amount”, as used herein, means an amounteffective in treating cancer, as defined immediately above.

An “astrocytoma” is a tumor composed of astrocytes. Astrocytes areneuroglial cells of ectodermal origin, characterized by fibrous,protoplasmic or plasmatofibrous processes.

APUDomas are tumors composed of APUD (amine precursor uptake anddecarboxylation) cells. APUD cells are found scattered throughout thebody (e.g., in the chromaffin system, hypothalamus, hypophysis, thyroid,parathyroids, lungs, gastrointestinal tract and pancreas) and areapparently unrelated but for sharing certain cytochemical andultrastructural characteristics. They synthesize structurally relatedpeptides (usually biogenic amines) that function as hormones orneurotransmitters (e.g., epinephrine, norepinephrine, dopamine,serotonin, enkalphalin, somatostatin, neurotensin and substance P). ADUPcells concentrate the amino acid precursors of these amines anddecarboxylate them to their respective amines.

More specifically, this invention relates to a method of treating cancerin a mammal, including a human, comprising administering to such mammala therapeutically effective amount of an NK-1 receptor antagonist thatis a compound of the formula

wherein A is a ring system selected from phenyl, naphthyl, thienyl,dihydroquinolinyl, quinolinyl and indolinyl, and wherein the sidechaincontaining NR²R³ is attached to a carbon atom of ring system A;

AA is an aryl group selected from phenyl, naphthyl, thienyl, quinolinyl,dihydroquinolinyl and indolinyl, and wherein the sidechain containingNR²R³ is attached to a carbon atom of AA;

AAA is an aryl group selected from phenyl, naphthyl, thienyl,dihydroquinolinyl, quinolinyl and indolinyl, and wherein the —CH₂PR³sidechain is attached to a carbon atom of ring AAA;

P is NR², O, S, SO or SO₂;

 wherein the point of attachment of said

 to ring AAA is the nitrogen atom and the point of attachment to X⁵ isthe sulfur atom;

W¹ and W² are selected, independently, from hydrogen, halo, (C₁-C₆)alkyl, S-(C₁-C₃)alkyl, and (C₁-C₆) alkoxy optionally substituted withfrom one to three fluorine atoms;

W is hydrogen, (C₁-C₆)alkyl optionally substituted with from one tothree fluorine atoms, —S(O)_(v)—(C₁-C₆) alkyl wherein v is zero, one ortwo, halo or (C₁-C₆)alkoxy optionally substituted with from one to threefluorine atoms;

X¹ is hydrogen, (C₁-C₁₀) alkoxy optionally substituted with from one tothree fluorine atoms or (C₁-C₁₀) alkyl optionally substituted with fromone to three fluorine atoms;

X² and X³ are independently selected from hydrogen, halo, nitro,(C₁-C₁₀) alkyl optionally substituted with from one to three fluorineatoms, (C₁-C₁₀) alkoxy optionally substituted with from one to threefluorine atoms, hydroxy, phenyl, cyano, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)alkylamino,

X⁵ is a four to six membered heterocyclic ring containing from one tofour heteroatoms selected from sulfur, nitrogen and oxygen (e.g.,thiazolyl, pyrrolyl, thienyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ringmay optionally be substituted with from one to three substituents,preferably with from zero to two substituents, independently selectedfrom phenyl, (C₁-C₆)alkyl optionally substituted with from one to threefluorine atoms, (C₁-C₆)alkoxy optionally substituted with from one tothree fluorine atoms and halo;

R is a 4, 5 or 6 membered heterocyclic ring containing from one to fourheteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl,azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein saidheterocyclic ring may contain from zero to three double bonds and mayoptionally be substituted with one or more substituents, preferably oneor two substituents, independently selected from (C₁-C₆) alkyloptionally substituted with from one to three fluorine atoms and (C₁-C₆)alkoxy optionally substituted with from one to three fluorine atoms;

R¹ is selected from amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,—S(O)_(v)-(C₁-C₁₀)-alkyl wherein v is zero, one or two, —S(O)_(v)-phenylwherein v is zero, one or two, —S(O)_(v)-benzyl wherein v is zero, oneor two, —O-phenyl, —O-benzyl, —SO₂NR⁴R⁵ wherein each of R⁴ and R⁵ is,independently, (C₁-C₆)alkyl, or R⁴ and R⁵, together with the nitrogen towhich they are attached, form a saturated ring containing one nitrogenand from 3 to 6 carbons,

 (C₁-C₁₀)alkyl wherein one or both of the alkyl moieties may optionallybe substituted with from one to three fluorine atoms,—N(SO₂-(C₁-C₁₀)alkyl)₂,

 and wherein any of the phenyl moieties in the foregoing R¹ groups mayoptionally be substituted with from one to three substituentsindependently selected from (C₁-C₄)alkyl, (C₁-C₄)alkoxy and halo;

or R¹ is phenyl substituted with a group having the formula

 wherein a is 0, 1 or 2 and the asterisk represents a bond to a positionmeta to the R²R³NCH₂ side chain;

the dotted lines in formula Ib represent that one of the X—Y and Y—Zbonds may optionally be a double bond;

X is selected from ═CH—, —CH₂—, —O—, —S—, —SO—, —SO₂—, —N(R⁴)—, —NH—,═N—, —CH [(C₁-C₆)alkyl]-, ═C[(C₁-C₆)alkyl]-, —CH(C₆H₅)— and ═C(C₆H₅)—;

Y is selected from C═O, C═NR⁴, C═S, ═CH—, —CH₂—, ═C[(C₁-C₆)alkyl]-,—CH[(C₁-C₆)alkyl]-, ═C(C₆H₅)—, —CH(C₆H₅)—, ═N—, —NH—, —N(R⁴)—,═C(halo)-, ═C(OR⁴)—, ═C(SR⁴)—, ═C(NR⁴)—, —O—, —S— and SO₂, wherein thephenyl moieties of said ═C(C₆H₅)— and —CH(C₆H₅)— may optionally besubstituted with from one to three substituents independently selectedfrom trifluoromethyl and halo, and wherein the alkyl moieties of said═[(C₁-C₆)alkyl]- and —CH[C₁-C₆)alkyl]- may optionally be substitutedwith from one to three fluorine atoms;

Z is selected from ═CH—, —CH₂—, ═N—, —NH—, —S—, —N(R⁴)—, ═C(C₆H₅)—,—CH(C₆H₅)—, ═C[(C₁-C₆)alkyl]- and —CH[(C₁-C₆)alkyl]-;

or X, Y and Z, together with the two carbon atoms shared between thebenzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;

R⁴ is (C₁-C₆) alkyl or phenyl, and each occurrence of R⁴ is independentof other occurrences of R⁴ in the same molecule;

R² is hydrogen or —CO₂(C₁-C₁₀)alkyl;

R³ is selected from

 wherein R⁶ and R¹⁰ are independently selected from furyl, thienyl,pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl mayoptionally be substituted with one or two substituents independentlyselected from halo, (C₁-C₁₀) alkyl optionally substituted with from oneto three fluorine atoms, (C₁-C₁₀) alkoxy optionally substituted withfrom one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C₁-C₃)alkoxy-carbonyl;

R⁷ is selected from (C₃-C₄) branched alkyl, (C₅-C₈) branched alkenyl,(C₅-C₇) cycloalkyl, and the radicals named in the definition of R⁶;

R⁸ is hydrogen or (C₁-C₆) alkyl;

R⁹ and R¹⁹ are independently selected from phenyl, biphenyl, naphthyl,pyridyl, benzhydryl, thienyl and furyl, and R⁹ and R¹⁹ may optionally besubstituted with from one to three substituents independently selectedfrom halo, (C₁-C₁₀) alkyl optionally substituted with from one to threefluorine atoms and (C₁-C₁₀) alkoxy optionally substituted with from oneto three fluorine atoms;

Y¹ is (CH₂), wherein I is an integer from one to three, or Y¹ is a groupof the formula J

Z¹ is oxygen, sulfur, amino, (C₁-C₃)alkylamino or (CH₂)_(k) wherein k iszero, one or two;

x is an integer from zero to four;

y is an integer from zero to four;

z is an integer from one to six, wherein the ring containing (CH₂)_(z)may contain from zero to three double bonds, and one of the carbons of(CH₂)_(z) may optionally be replaced by oxygen, sulfur or nitrogen;

o is two or three;

p is zero or one;

r is one, two or three;

R¹¹ is thienyl, biphenyl or phenyl optionally substituted with one ortwo substituents independently selected from halo, (C₁-C₁₀) alkyloptionally substituted with from one to three fluorine atoms and(C₁-C₁₀) alkoxy optionally substituted with from one to three fluorineatoms;

X⁴ is (CH₂)_(q) wherein q is an integer from 1 to 6, and wherein any oneof the carbon-carbon single bonds in said (CH₂)_(q) may optionally bereplaced by a carbon-carbon double bond, and wherein any one of thecarbon atoms of said (CH₂)_(q) may optionally be substituted with R¹⁴,and wherein any one of the carbon atoms of said (CH₂)_(q) may optionallybe substituted with R¹⁵;

m is an integer from 0 to 8, and any one of the carbon-carbon singlebonds of (CH₂)_(m), wherein both carbon atoms of such bond are bonded toeach other and to another carbon atom in the (CH₂)_(m) chain, mayoptionally be replaced by a carbon-carbon double bond or a carbon-carbontriple bond, and any one of the carbon atoms of said (CH₂)_(m) havingthe requisite available bonding sites may optionally be substituted withR¹⁷;

R¹² is a radical selected from hydrogen, (C₁-C₆) straight or branchedalkyl, (C₃-C₇)cycloalkyl wherein one of the carbon atoms may optionallybe replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl,phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl-(C₂-C₆)alkyl, benzhydryl and benzyl,wherein the point of attachment on R¹² is a carbon atom unless R¹² ishydrogen, and wherein each of said aryl and heteroaryl groups and thephenyl moieties of said benzyl, phenyl-(C₂-C₆)alkyl and benzhydryl mayoptionally be substituted with one or more substituents 20 independentlyselected from halo, nitro, (C₁-C₁₀)alkyl optionally substituted withfrom one to three fluorine atoms, (C₁-C₁₀)aikoxy optionally substitutedwith from one to three fluorine atoms, amino, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C₁-C₆)alkyl, (C₁-C₆)-alkylamino,

 and wherein one of the phenyl moieties of said benzhydryl mayoptionally be replaced by naphthyl, thienyl, furyl or pyridyl;

R¹³ is hydrogen, phenyl or (C₁-C₆)alkyl;

or R¹² and R¹³, together with the carbon to which they are attached,form a saturated carbocyclic ring having from 3 to 7 carbon atomswherein one of said carbon atoms that is neither the point of attachmentof the spiro ring nor adjacent to it may optionally be replaced byoxygen, nitrogen or sulfur;

R¹⁴ and R¹⁵ are each independently selected from hydrogen, hydroxy,halo, amino, oxo (═O), cyano, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C₁-C₆)alkyl, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₁-C₆)alkoxy,

 and the radicals set forth in the definition of R¹²;

 NHCH₂R¹⁸, SO₂R¹⁸, GR²⁰, CO₂H or one of the radicals set forth in any ofthe definitions of R¹², R¹⁴ and R¹⁵;

R¹⁷ is oximino (═NOH) or one of the radicals set forth in any of thedefinitions of R¹², R¹⁴ and R¹⁵; and

R¹⁸ is (C₁-C₆)alkyl, hydrogen, phenyl or phenyl (C₁-C₆)alkyl;

G is selected from the group consisting of CH₂, nitrogen, oxygen, sulfurand carbonyl;

R²⁰ is a monocyclic or bicyclic heterocycle selected from the groupconsisting of pyrimidinyl, benzoxazolyl,2,3dihydro-3oxobenzisosulfonazol-2-yl, morpholin-1-yl,thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl,isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl,tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae

 wherein B and D are selected from carbon, oxygen, and nitrogen, and atleast one of B and D is other than carbon; E is carbon or nitrogen; n isan integer from 1 to 5; and any one of the carbons of the (CH₂)_(n) or(CH₂)_(n+1) may be optionally substituted with (C₁-C₆)alkyl or (C₂-C₆)spiroalkyl, and either any two of the carbon atoms of said (CH₂)_(n) and(CH₂)_(n+1) may be bridged by a one or two carbon atom linkage, or anyone pair of adjacent carbons of said (CH₂)_(n) and (CH₂)_(n+1) may form,together with from one to three carbon atoms that are not members of thecarbonyl containing ring, a (C₃-C₅) fused carbocyclic ring;

with the proviso that (a) when m is 0, one of R¹⁶ and R¹⁷ is absent andthe other is hydrogen, (b) when R³ is a group of the formula VIII, R¹⁴and R¹⁵ cannot be attached to the same carbon atom, (c) when R¹⁴ and R¹⁵are attached to the same carbon atom, then either each of R¹⁴ and R¹⁵ isindependently selected from hydrogen, fluoro, (C₁-C₆)alkyl,hydroxy-(C₁-C₆)alkyl and (C₁-C₆)aikoxy-(C₁-C₆)alkyl, or R¹⁴ and R¹⁵,together with the carbon to which they are attached, form a (C₃-C₆)saturated carbocyclic ring that forms a spiro compound with thenitrogen-containing ring to which they are attached; (d) R¹² and R¹³cannot both be hydrogen; (e) when R¹⁴ or R¹⁵ is attached to a carbonatom of X⁴ of group VII or to a carbon atom of (CH₂)_(y) of group VIIIthat is adjacent to the ring nitrogen, then R¹⁴ or R¹⁵, respectively,must be a substituent wherein the point of attachment is a carbon atom;(f) when said compound is a group of the formula Id or a group of theformula Ic or Ie wherein M or AAA, respectively, is phenyl optionallysubstituted with 1, 2 or 3 groups selected from (C₁-C₆)alkyl,trifluoromethyl, halo, cyano, nitro, (C₁-C₆)alkoxy, trifluoromethoxy,and —S(O)_(v)-(C₁-C₁₀)alkyl wherein v is zero, one or two, and R³ is agroup of the formula VII wherein R¹³ is hydrogen and R¹² is phenyl,naphthyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl,benzhydryl or benzyl, and R¹² is optionally substituted with(C₁-C₆)alkyl, trifluoromethyl, (C₁-C₆)alkoxy or halo, then at least oneof R¹⁴ and R¹⁵ must be other than hydrogen, (C₁-C₆)alkyl, oxo, halo,—COOH, —COO(C₁-C₆)alkyl or phenyl optionally substituted with(C₁-C₆)alkyl, halo or trifluoromethyl; and (g) neither R¹⁴, R¹⁵, R¹⁶ norR¹⁷ can form a ring with R¹³;

or a pharmaceutically acceptable salt of such compound.

The fused bicyclic nucleus of compounds of the formula Ib to which W andthe —CN₂NR²R³ sidechain are attached may be, but is not limited to oneof the following groups: benzoxazolyl, benzothiazolyl, benzimidazolyl,benzisoxazolyl, benzisothiazolyl, indazolyl, indolyl, isoquinolinyl,benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl,benzothiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl,dihydrobenzothienyl-S,S-dioxide, benzotriazolyl, benzothiadiazolyl,benzoxadiazolyl, and quinazolinyl.

The term “halo”, as used herein, unless otherwise indicated, includeschloro, fluoro, bromo and iodo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term “alkoxy”, as used herein, includes O-alkyl groups wherein“alkyl” is defined as above.

The term “one or more substituents,” as used herein, includes from oneto the maximum number of substituents possible based on the number ofavailable bonding sites.

More specific embodiments of this invention relate to the above methodof treating cancer, wherein the NK-1 receptor antagonist is a compoundas defined in any of paragraphs (1) through (42) below, or apharmaceutically acceptable salt of such compound.

(1) A compound of the formula Ia or Ib wherein the substituents atpositions “2” and “3” of the nitrogen containing ring of R³ are in a cisconfiguration. (When R³ is a group of the formula VII or VIII, “a cisconfiguration”, as used herein, means that the non-hydrogen substituentat position “3” is cis to R¹²).

(2) A compound of the formula Ia wherein R³ is a group of the formulaIII, VII or IX; R² is hydrogen; A is phenyl or indolinyl; W is(C₁-C₃)alkoxy optionally substituted with from one to five fluorineatoms; and R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl oroxazolyl, and R may optionally be substituted with one or two (C₁-C₃)alkyl moieties.

(3) A compound of the formula Ib wherein R³ is a group of the formulaIIII, VII or IX; R² is hydrogen; the fused bicyclic ring system to whichW and the —CH₂NR²R³ sidechain are attached is benzoxazolyl,benzisoxazolyl, benzothiazolyl or benzimidazolyl; and W is (C₁-C₆)alkoxyoptionally substituted with from one to five fluorine atoms.

(4) A compound as defined in paragraph 1, 2 or 3 above wherein: (a) R³is a group of the formula III and R⁹ is benzhydryl; (b) R³ is a group ofthe formula VII, R¹² is phenyl, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ ishydrogen, m is zero and X⁴ is —(CH₂)₃—; or (c) R³ is a group of theformula IX, r is two and R¹⁹ is benzhydryl.

(5) A compound of the formula Ia wherein: (a) R³ is a group of theformula III wherein the substituents at positions “2” and “3” of thenitrogen containing ring are in the cis configuration, R⁹ is benzhydryland A is phenyl; or (b) R³ is a group of the formula VII wherein R¹² andthe substituent at position “3” of the nitrogen containing ring are inthe cis configuration, A is phenyl, R¹² is phenyl, each of R², R¹³, R¹⁴,R¹⁵ and R¹⁶ is hydrogen, m is zero, W is methoxy or isopropoxy, X⁴ is—(CH₂)₃— and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl orthiadiazolyl.

(6) A compound of the formula Ib wherein R³ is a group of the formula IXwherein the substituents at positions “2” and “3” of the nitrogencontaining ring are in the cis configuration, R¹⁹ is benzhydryl, r istwo and the fused bicyclic ring system to which W and the —CH₂NR²R³sidechain are attached is benzisoxazolyl or benzothiazolyl.

(7) A compound of the formula Ib wherein R³ is a group of the formulaIX, R¹⁹ is benzhydryl, the fused bicyclic ring system to which W and the—CH₂NR²R³ sidechain are attached is benzisoxazolyl, and W is methoxy.

(8) A compound of the formula Ib wherein R³ is a group of the formulaVII, R¹² is phenyl, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m iszero, X⁴ is —(CH₂)₃—, and the fused bicyclic ring system to which W andthe —CH₂NR²R³ sidechain are attached is benzothiazolyl, benzoxazolyl orbenzimidazolyl.

(9) A compound of the formula Ia wherein R³ is a group of the formulaVII, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m is zero, X⁴ is—(CH₂)₃—, A is phenyl, W is methoxy, and R is selected from thiazolyl,imidazolyl, thiadiazolyl and isoxazolyl.

(10) A compound of the formula Ic, wherein R³ is a group of the formulaII, III, VII or IX; R² is hydrogen; ring AA is phenyl or indolinyl; WIis (C₁-C₃)alkoxy optionally substituted with from one to three fluorineatoms; and R¹ is S(O)_(v)-(C₁-C₁₀)alkyl wherein v is zero, one or two,S(O)_(v)-aryl wherein v is zero, one or two, —O-aryl,

wherein one or both of the alkyl moieties may optionally be substitutedwith from one to three fluorine atoms, —N(SO₂-(C₁-C₁₀)alkyl)₂ or

wherein said aryl is phenyl or benzyl and may optionally be substitutedwith from one to three substituents independently selected from(C₁-C₄)alkyl, (C₁-C₄)alkoxy and halo.

(11) A compound as defined in paragraph 10 above, wherein R³ is a groupof the formula II, o is two, and each R⁶ and R⁷ is phenyl.

(12) A compound as defined in paragraph 10 above, wherein R³ is a groupof the formula VII, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, R¹² isphenyl, m is zero and X⁴ is —(CH₂)₃—.

(13) A compound as defined in paragraph 10 above, wherein R³ is a groupof the formula IX, R¹⁹ is benzhydryl and r is two.

(14) A compound as defined in paragraph 10 above, wherein R³ is a groupof the formula III, R⁸ is other than hydrogen and R⁹ is benzyhydryl.

(15) A compound of the formula Ic wherein the substituents at positions“2” and “3” of the nitrogen containing ring of R³ are in the cisconfiguration.

(16) A compound of the formula Ic wherein R³ is a group of the formulaII wherein the substituents at positions “2” and “3” of the nitrogencontaining ring are in the cis configuration, o is two, each of R⁶ andR⁷ is phenyl and ring AA is phenyl or indolinyl.

(17) A compound of the formula Ic wherein R³ is a group of the formulaIII wherein the substituents at positions “2” and “3” of the nitrogencontaining ring are in the cis configuration, R⁸ is other than hydrogen,R⁹ is benzhydryl and ring AA is phenyl.

(18) A compound of the formula Ie wherein R³ is a group of the formulaVII wherein R¹² and the substituent at position “3” of the nitrogencontaining ring are in the cis configuration, ring AA is phenyl, R¹² isphenyl, each of R², R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m is zero, X⁴ is—(CH₂)₂— or —(CH₂)₃— and R¹ is selected from S(O)_(v)-(C₁-C₁₀)alkylwherein v is zero, one or two,

and di-(C₁-C₆)alkylamino.

(19) A compound as defined in paragraph 18 above, wherein X⁴ is —(CH₂)₂—and W¹ is (C₁-C₆) alkoxy optionally substituted with from one to threefluorine atoms.

(20) A compound as defined in paragraph 18 above, wherein X⁴ is —(CH₂)₃—and W¹ is (C₁-C₆) alkoxy optionally substituted with from one to threefluorine atoms.

(21) A compound of the formula Ic, wherein R³ is a group of the formulaIX wherein the substituents at positions “2” and “3” of the nitrogencontaining ring are in the cis configuration, r is two and R¹⁹ isbenzhydryl.

(22) A compound as defined in paragraph 21 above, wherein ring AA isphenyl, W¹ is (C₁-C₆) alkoxy optionally substituted with from one tothree fluorine atoms and R¹ is selected from —S(O)_(v)-(C₁-C₁₀)alkylwherein v is zero, one or two, (C₁-C₆)alkylamino, di-(C₁-C₆) alkylaminoand

(23) A compound as defined in paragraph 15 above, wherein ring AA isphenyl, W¹ is (C₁-C₆)alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from —S(O)_(v)-(C₁-C₁₀)alkylwherein v is zero, one or two, and

(24) A compound as defined in paragraph 15 above, wherein ring AA isphenyl, W¹ is (C₁-C₆)alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from amino, (C₁-C₆)alkylaminoand di-(C₁-C₆)alkylamino.

(25) A compound as defined in paragraph 12 above, wherein ring AA isphenyl and R¹ is selected from —S(O)_(v)-(C₁-C₁₀)alkyl wherein v iszero, one or two, and

(26) A compound of the formula Ic wherein R³ is a group of the formulaIII, ring AA is phenyl, W¹ is (C₁-C₆)alkoxy optionally substituted withfrom one to three fluorine atoms, and R¹ is selected from amino,(C₁-C₆)alkylarnino or di-(C₁-C₆)alkylamino.

(27) A compound as defined in paragraph 24 above, wherein W¹ is attachedat the “2” position of ring M and R¹ is attached at the “5” position ofring AA, relative to the point of attachment of the NR²R³ containingside chain.

(28) A compound as defined in paragraph 25 above, wherein W¹ is attachedat the “2” position of ring AA and R¹ is attached at the “5” position ofring AA, relative to the point of attachment of the NR²R³ containingside chain.

(29) A compound as defined in paragraph 26 above, wherein W¹ is attachedat the “2” position of ring AA and R¹ is attached at the “5” position ofring AA, relative to the point of attachment of the NR²R³ containingside chain.

(30) A compound as defined in paragraph 23 above, wherein W¹ is attachedat the “2” position of ring AA and R¹ is attached at the “5” position ofring AA, relative to the point of attachment of the NR²R³ containingside chain.

(31) A compound as defined in paragraph 13 above, wherein ring AA isphenyl, W¹ is selected from isopropoxy, OCF₃, OCH₃, OCHF₂ and OCH₂CF₃,and R¹ is selected from —S(O)_(v)-(C₁-C₁₀)alkyl wherein v is zero, oneor two, and (C₁-C₁₀)alkyl-N—SO-(C₁-C₁₀)alkyl.

(32) A compound of the formula Ic, wherein R³ is a group of the formulaVII, m is zero, each of R¹³, R¹⁵, R¹⁶ and R¹⁷ is hydrogen, R¹² isphenyl,

ring AA is phenyl, W¹ is (C₁-C₃)alkoxy and R¹ is selected from(C₁-C₅)alkyl, —SCH₃, SO₂CH₃, SOCH₃, (C₁-C₆)alkylamino anddi-(C₁-C₆)alkylamino.

(33) A compound of the formula Ic, having the formula

(34) A compound of the formula Id wherein R⁶, R⁷, R¹⁰, R¹¹ and R¹³ arephenyl, R⁸ is hydrogen, R⁹ is phenyl optionally substituted withchlorine, fluorine, (C₁-C₆) alkyl optionally substituted with from oneto three fluorine atoms or (C₁-C₆) alkoxy optionally substituted withfrom one to three fluorine atoms, m is 0 and k is 3 or 4.

(35) A compound of the formula Id, wherein R³ is a group of the formulaII wherein o is two or three and each of R⁶ and R⁷ is phenyl orsubstituted phenyl.

(36) A compound of the formula Id, wherein R³ is a group of the formulaIII, R⁸ is hydrogen and R⁹ is phenyl or substituted phenyl.

(37) A compound of the formula Id, wherein R³ is a group of the formulaIV wherein I is one or two and each of R¹⁰ and R¹¹ is phenyl orsubstituted phenyl.

(38) A compound of the formula Id, wherein R³ is a group of the formulaV wherein k is zero or one and each of R¹⁰ and R¹¹ is phenyl orsubstituted phenyl.

(39) A compound of the formula Id, wherein R³ is a group of the formulaVI wherein p is one and each of R¹⁰ and R¹¹ are phenyl or substitutedphenyl.

(40) A compound of the formula Id, wherein R³ is a group of the formulaVII wherein q is two, three or four, m is zero and R¹² is phenyl orsubstituted phenyl.

(41) A compound of the formula Id, wherein R³ is a group of the formulaVIII wherein y is zero, x is zero or one, z is three or four, m is zeroand R¹² is phenyl or substituted phenyl.

(42) A compound of the formula Id wherein R³ is a group of the formulaVII, R¹⁴, R¹³, R¹⁶ and R¹⁵ are hydrogen, R¹² is phenyl, X¹ is 2-methoxy,X² and X³ are independently selected from hydrogen, chlorine, fluorine,methyl, (C₁-C₆)alkoxy and trifluoromethyl, m is 0 and q is 3 or 4.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound having the formula

wherein W is Y or X(CH₂)_(n);

Y is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₂-C₆)alkenyl or optionally substituted (C₃-C₈)cycloalkyl;

X is optionally substituted (C₁-C₆)alkoxy, hydroxy, CONR¹R², CO₂R¹,CHR¹OR², CHR¹NR²R³, COR¹, CONR¹OR² or optionally substituted aryl,wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl and pyrazolyl; and n is an integer from zero to six;

Ar¹, Ar² and Ar³ are each, independently, optionally substituted aryl,wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl and pyrazolyl;

and R¹, R² and R³ are independently selected from hydrogen, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkoxy,optionally substituted (C₃-C₈)cycloalkyl, optionally substituted aryl,wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl and pyrazolyl; and optionally substituted (C₃-C₅)heterocyclicgroups, wherein said heterocyclic groups are selected from pyrrolidino,piperidino, morpholino, piperazinyl and thiamorpholino;

and wherein the substituents on the foregoing substituted alkyl,alkenyl, cycloalkyl and alkoxy groups are independently selected fromhalo, nitro, amino, (C1-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl andtrifluoromethoxy;

and wherein the substituents on the foregoing substituted (C₃-C₅)heterocyclic groups are attached to a sulfur or nitrogen atom on thering and are independently selected from oxygen, di-oxygen and(C₁-C₄)alkyl when attached to a ring sulfur atom, and are independentlyselected from oxygen and (C₁-C₄)alkyl when attached to a ring nitrogenatom;

and wherein the substituents on said substituted Ar¹ groups areindependently selected from (C₁-C₆)alkyl optionally substituted withfrom one to three halo groups, (C₁-C₆)alkoxy optionally substituted withfrom one to three halo groups, (C₁-C₆)alkylsulfinyl, (C₂-C₆)alkenyl,(C₁-C₆)alkylthio, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylsulfonylamino, anddi-(C₁-C₆)alkylamino wherein one or both of the alkyl groups may beoptionally substituted with a (C₁-C₆,)alkylsulfonyl, or(C₁-C₆)alkylsulfinyl group;

and wherein the substituents on said substituted Ar² and Ar³ groups areindependently selected from (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, di-(C₁-C₄)alkylamino,trifluoromethyl and trifluoromethoxy; with the proviso that when Y isunsubstituted or is substituted with (C₁-C₄)alkyl, it is attached to the4- or 6-position of the quinuclidine ring;

or a pharmaceutically acceptable salt of such compound.

Other more specific embodiments of this invention relate to the methodof treating cancer described immediately above, wherein the NK-1receptor antagonist is a compound as defined in any of paragraphs (43)through (48) below, or a pharmaceutically acceptable salt of suchcompound.

(43) A compound of the formula X, wherein W is X(CH₂)_(n).

(44) A compound of the formula X, wherein W is Y.

(45) A compound of the formula X, wherein Ar¹ is substituted aryl and Wis Y.

(46) A compound of the formula X, wherein Ar¹ is mono-, di- ortn-substituted phenyl and W is Y.

(47) A compound of the formula X, wherein Ar¹ is phenyl disubstituted atthe 2- and 5-positions and W is Y.

(48) A compound of the formula X, wherein Ar¹ is para-methoxyphenyl,each of Ar² and Ar³ is phenyl and W is Y.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective mount of an NK-1 receptor antagonist that is acompound of the formula

wherein X¹ is C₁-C₅ alkoxy or halosubstituted (C₁-C₅) alkoxy;

X² is hydrogen, halogen, (C₁-C₅)alkyl, (C₂-C₅)alkenyl, (C₂-C₅)alkynyl,(C₁-C₅)alkoxy, (C₁-C5)alkylthio, (C₁-C₅) alkylsulfinyl, (C₁-C₅)alkylsulfonyl, halosubstituted (C₁-C₅) alkyl, halosubstituted (C₁-C₅)alkoxy, (C₁-C₅)alkylamino, dialkylamino having from 1 to 5 carbon atomsin each alkyl moiety, (C₁-C₅)alkylsulfonylamino (which may besubstituted by halogen),

 (which may be substituted by halogen in the alkylsulfonyl moiety),(C₁-C₅)alkanoylamino (which may be substituted by halogen) or

 (which may be substituted by halogen in the alkanoyl moiety);

Ar¹ and Ar² are each, independently, thienyl, phenyl, fluorophenyl,chlorophenyl or bromophenyl;

W³ is Y—(CH₂)_(m)—CH(R²)—(CH₂)_(n)—NR¹;

R¹ is hydrogen, (C₁-C₅)alkyl, benzyl or —(CH₂)_(p)—Y;

R² is hydrogen, (C₁-C₅)alkyl (which may be substituted by a substituentselected from the group consisting of hydroxy, amino, methylthio andmercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or —(CH₂)_(p)—Y;

Y is —CN, —CH₂Z or —COZ;

Z is hydroxy, amino, (C₁-C₅)alkoxy, (C₁-C₅) alkylamino or dialkylaminohaving from 1 to 5 carbon atoms in each alkyl moiety;

m, n and p are each, independently, 0, 1, 2 or 3; and

R¹ and R² may be connected to form a ring;

or a pharmaceutically acceptable salt of such compound.

The terms “halogen” or “halo” is used above for formula XV to meanfluoro, chloro, bromo or iodo.

The term “alkyl” is used above for formula XV to mean straight orbranched hydrocarbon chain radicals including, but not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,and the like.

The term “alkenyl” is used above for formula XV to mean straight orbranched hydrocarbon chain radicals having one double bond including,but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1-and 2-butenyl and the like.

The term “alkynyl” is used above for formula XV to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl and the like.

The term “alkoxy” is used above for formula XV to mean —OR³ (R³ isalkyl) including, but not limited to, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy and the like.

The term “alkylthio” is used above for formula XV to mean —SR⁴ (R⁴ isalkyl) including but not limited to, methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio,t-butylthio and the like.

The term “alkylsulfinyl” is used above for formula XV to mean —SOR⁵ (R⁵is alkyl) including, but .limited to, methylsulfinyl, ethylsulfinyl,propylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl,t-butylsulfinyl and the like.

The term “alkylsulfonyl” is used above for formula XV to mean —SO₂R⁶ (R⁶is alkyl) including, but limited to, methylsulfonyl, ethylsulfonyl,propylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl,t-butylsulfonyl and the like.

The term “alkylsulfonylamino (which may be substituted by halogen)” isused above for formula XV to mean —NHSO₂R⁷ (R⁷ is alkyl which may besubstituted by halogen) including, but not limited to,methylsuflonylamino, ethylsulfonylamino, trifluoromethylsulfonylaminoand the like.

The term “N-alkyl-N-alkylsulfonylamino (which may be substituted byhalogen in the alkylsulfonyl moiety)” is used above for formula XV tomean —N(R⁸)SO₂R⁹ (R⁸ is alkyl and R⁹ is alkyl which may be substitutedby halogen) including, but not limited to, N-methyl-N-methylsulfonylamino, N-ethyl-N-methylsulfonylamino,N-n-propyl-N-methylsulfonylamino, N-isopropyl-N-methylsulfonylamino,N-methyl-N-trifluoromethylsulfonylamino,N-ethyl-N-trifluoromethylsulfonylamino,N-n-propyl-N-trifluoromethylsulfonylamino,N-isopropyl-N-trifluoromethylsulfonylamino and the like.

The terms “alkylamino” and “dialkylamino” are used above for formula XVto mean —N(R¹⁰)R¹¹ (R¹⁰ is hydrogen or alkyl and R¹¹ is alkyl)including, but not limited to, methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, t-butylamino, dimethylamino, diethylamino,ethylmethylamino and the like.

The term “alkanoylamino (which may be substituted by halogen)” is usedabove for formula XV to mean —NHCOR¹² (R¹² is alkyl which may besubstituted by halogen) including, but not limited to, formylamino,acetylamino, propionylamino, butyrylamino, isobutyrylamino,trifluoroacetylamino and the like.

The term “N-alkyl-N-alkanoylamino (which may be substituted by halogenin the alkanoyl moiety)” is used above for formula XV to mean—N(R¹³)COR¹⁴ (R¹³ is alkyl and R¹⁴ is alkyl which may be substituted byhalogen) including, but not limited to, N-acetyl-N-methylamino,N-acetyl-N-ethylamino, N-acetyl-N-n-propylamino,N-acetyl-N-isopropylamino, N-trifluoroacetyl-N-methylamino,N-trifluoroacetyl-N-ethylamino, N-trifluoroacetyl-N-n-propylamino,N-trifluoroacetyl-N-isopropylamino and the like;

The term “halosubstituted alkyl” is used above for formula XV to mean analkyl radical as described above substituted with one or more halogensincluding, but not limited to, chloromethyl, trifluoromethyl,2,2,2-trichloroethyl and the like.

The term “halosubstituted alkoxy” is used above for formula XV to meanan alkoxy radical as described above substituted with one or morehalogens including, but not limited to, chloromethoxy, trifluoromethoxy,2,2,2-trichloroethoxy and the like.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein R¹ is phenyl optionally substituted with one or moresubstituents, preferably with from one to three substituents,independently selected from hydrogen, halo, nitro, (C₁-C₁₀) alkyloptionally substituted with from one to three fluorine atoms, (C₁-C₁₀)alkoxy optionally substituted with from one to three fluorine atoms,hydroxy, phenyl, cyano, amino, (C₁-C₆)-alkylamino, di-(C₁-C₆)alkylamino,—C—NH-(C₁-C₆) alky,

(C₁-C₄)alkoxy(C₁-C₄)alkyl, —S(O)_(v)-(C₁-C₁₀)-alkyl wherein v is zero,one or two, —S(O)_(v)-phenyl wherein v is zero, one or two,—S(O)_(v)-benzyl wherein v is zero, one or two, —O-phenyl, —O-benzyl,—SO₂NR⁴R⁵ wherein each of R⁴ and R⁵ is, independently, (C₁-C₆)alky, orR⁴ and R⁵, together with the nitrogen to which they are attached, form asaturated ring containing one nitrogen and from 3 to 6 carbons,

wherein one or both of the alkyl moieties may optionally be substitutedwith from one to three fluorine atoms, —N(SO₂-(C₁-C₁₀)alkyl)₂,

and wherein any of the phenyl moieties in the foregoing R¹ groups mayoptionally be substituted with from one to three substituentsindependently selected from (C₁-C₄)alkyl, (C₁-C₄)alkoxy and halo;

or R¹ is phenyl substituted with a group having the formula

 wherein a is 0, 1 or 2 and the asterisk represents a bond to a positionmeta to the point of attachment of R¹ to structure XVI;

R² is selected from (C₁-C₆) straight or branched alkyl, (C₃-C₇)cycloalkyl wherein one of the carbon atoms may optionally be replaced bynitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyland naphthyl; heteroaryl selected from thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl andquinolyl; phenyl (C₂-C₆) alkyl, benzhydryl and benzyl, wherein each ofsaid aryl and heteroaryl groups and the phenyl moieties of said benzyl,phenyl (C₂-C₆) alkyl and benzhydryl may optionally be substituted withone or more substituents, preferably with from one to threesubstituents, independently selected from halo, nitro, (C₁-C₁₀) alkyloptionally substituted with from one to three fluorine atoms, (C₁-C₁₀)alkoxy optionally substituted with from one to three fluorine atoms,amino, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,(C₁-C₆)-alkylamino,

 and wherein one of the phenyl moieties of said benzhydryl mayoptionally be replaced by naphthyl, thienyl, furyl or pyridyl;

m is an integer from 0 to 8, and any one of the carbon—carbon singlebonds of (CH₂)_(m), wherein both carbon atoms of such bond are bonded toeach other and to another carbon atom in the (CH₂)_(m) chain, mayoptionally be replaced by a carbon—carbon double bond or a carbon—carbontriple bond, and any one of the carbon atoms of said (CH₂)_(m) mayoptionally be substituted with R⁴;

R³ is selected from

 NHCH₂R⁸, SO₂R⁸, AR⁹, CO₂H and the radicals set forth in the definitionsof R², R⁶ and R⁷;

A is CH₂, nitrogen, oxygen, sulfur or carbonyl;

R⁴ is selected from oximino (═NOH) and the radicals set forth in thedefinitions of R², R⁶ and R⁷;

R⁸ is (C₁-C₆)alkyl, hydrogen, phenyl or phenyl (C₁-C₆)alkyl;

R⁹ is a monocyclic or bicyclic heterocycle selected from the groupconsisting of pyrimidinyl, benzoxazolyl,2,3dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl,thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl,isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl,tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae

 wherein B and D are selected from carbon, oxygen and nitrogen, and atleast one of B and D is other than carbon; E is carbon or nitrogen; n isan integer from 1 to 5; any one of the carbon atoms of said (CH₂)_(n)and (CH₂)_(n+1) may be optionally substituted with (C₁-C₆)alkyl or(C₂-C₆) spiroalkyl; and either any one pair of the carbon atoms of said(CH₂)_(n) and (CH₂)_(n+1) may be bridged by a one or two carbon atomlinkage, or any one pair of adjacent carbon atoms of said (CH₂)_(n) and(CH₂)_(n+1) may form, together with from one to three carbon atoms thatare not members of the carbonyl containing ring, a (C₃-C₅) fusedcarbocyclic ring;

X is (CH₂)_(q) wherein q is two or three and wherein one of thecarbon-carbon single bonds in said (CH₂)_(q) may optionally be replacedby a carbon-carbon double bond, and wherein any one of the carbon atomsof said (CH₂)_(q) may optionally be substituted with R⁶, and wherein anyone of the carbon atoms of said (CH₂)_(q) may optionally be substitutedwith R⁷;

R⁶ and R⁷ are independently selected from hydrogen, hydroxy, halo,amino, oxo (═O), cyano, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C₁-C₆)alkyl, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino,(C₁-C₆)alkoxy,

 and the radicals set forth in the definition of R²; and

Y is (CH₂)_(z) wherein z is zero or one;

with the proviso that: (a) when A is —(CH₂)— or carbonyl, R⁹ cannot befuryl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl,thiazolyl or thienyl; (b) when m is zero, one of R³ and R⁴ is absent andthe other is hydrogen; (c) when R⁶ or R⁷ is attached to a carbon atom ofX that is adjacent to the ring nitrogen, then R⁶ or R⁷, respectively,must be a substituent wherein the point of attachment is a carbon atom;and (d) when A is N, O or S, R⁹ is not morpholin-1-yl orthiomorpholin-1-yl;

or a pharmaceutically acceptable salt of such compound.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein Ar¹ and Ar² are each independently aryl or substituted aryl;

R¹ is alkyl having from 1 to 6 carbon atoms;

R² is hydrogen or alkyl having from 1 to 6 carbon atoms;

and either X and Y are taken separately and they are each,independently, hydrogen, dialkylphosphoryl having from 2 to 12 carbonatoms, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6carbon atoms or alkynyl having from 2 to 6 carbon atoms; or X and Y aretaken together and they represent a hydrocarbon chain having 3, 4, or 5carbon atoms, optionally containing up to 2 double bonds and optionallyhaving 1 or 2 substituents selected from oxo, hydroxy and alkyl havingfrom 1 to 6 carbon atoms;

provided that when X and Y are taken together they are attached toadjacent carbon atoms; and

provided that if either X or Y is hydrogen, then the other one must bealkenyl or alkynyl;

or a pharmaceutically acceptable salt of such compound.

The term “alkyl” is used above for formula XVII to mean straight orbranched hydrocarbon chain radicals including, but not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and thelike.

The term “alkenyl” is used above for formula XVII to mean straight orbranched hydrocarbon chain radicals having one double bond including,but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1-and 2-butenyl and the like.

The term “alkynyl” is used above for formula XVII to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl and the like.

The term “aryl” is used above for formulae XVII to mean aromaticradicals including, but not limited to, phenyl, naphthyl, pyridyl,quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl,pyrazolyl and the like. There may be mentioned alkyl, alkoxy, alkylthio,halogen, cyano, nitro, phenoxy, mono- or dialkylamino and the like asthe substituents on the aryl.

The term “alkoxy” is used above for formula XVII to mean —OR³ (R³ isalkyl) including, but not limited to, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.

The term “halogen” is used above for formula XVII to mean radicalsderived from the elements fluorine, chlorine, bromine and iodine.

The term “alkylthio” is used in formula XVII to mean —SR⁴ (R⁴ is alkyl)including, but not limited to, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, t-butylthio and the like.

The term “dialkylphosphoryl” is used in formula XVII to mean—P(O)(OR⁵)(OR⁶) (R⁵ and R⁶ are alkyl) including, but not limited to,diethylphosphoryl, ethylmethylphosphoryl and the like.

Other more specific embodiments of this invention relate to the methodof treating cancer described immediately above, wherein the NK-1receptor antagonist that is administered is a compound as defined in anyof paragraphs (49)-(51) below, or a pharmaceutically acceptable salt ofsuch compound.

(49) Compounds of formula XVII wherein Ar¹ and Ar² are each phenyl, R¹is methyl, R² is hydrogen, X is alkenyl or alkynyl and Y is hydrogen.

(50) Compounds of the formula XVII wherein Ar¹ and Ar² are each phenyl,R¹ is methyl, R² is hydrogen and X and Y are each alkyl.

(51) Compounds of the formula XVII wherein Ar¹ and Ar² are each phenyl,R¹ is methyl, R² is hydrogen and X and Y represent CH₂CH₂CH₂ orCH₂CH₂CH₂CH₂.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein Ar¹ and Ar² are each, independently, thienyl, phenyl,fluorophenyl, chlorophenyl or bromophenyl;

X is —CONR³R⁴, —CO₂R³, —CH₂OR³, —CH₂NR³R⁴ or —CONR³OR⁴;

R¹, R³ and R⁴ are each, independently, hydrogen or alkyl having 1 to 4carbon atoms;

R² is alkyl having 1 to 4 carbon atoms;

Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkyl-N-alkanoylamino(which may be substituted by halogen in the alkanoyl moiety) having 1 to4 carbon atoms in the alkyl and the alkanoyl moieties,N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in thealkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and thealkylsulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynylhaving 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbonatoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which maybe substituted by halogen) having 1 to 4 carbon atoms oralkylsulfonylamino (which may be substituted by halogen) having 1 to 4carbon atoms;

or a pharmaceutically acceptable salt of such compound.

The term “alkyl” is used above for formula XVIII to mean straight orbranched hydrocarbon chain radicals including, but not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and thelike;

The term “alkenyl” is used above for formula XVIII to mean straight orbranched hydrocarbon chain radicals having one double bond including,but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1-and 2-butenyl and the like.

The term “alkynyl” is used above for formula XVIII to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl and the like.

The term “alkylsulfonyl” is used above for formula XVIII to mean —SO₂R⁵(R⁵ is alkyl) including, but not limited to, methylsulfonyl,ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butyl sulfonyl,isobutylsulfonyl, t-butylsulfonyl and the like.

The term “alkylamino” is used above for formula XVIII to mean —NHR⁶ (R⁶is alkyl) including, but not limited to, methylamino, ethylamino,n-propylamino, isopropylamino, n-butylamino, t-butylamino and the like.

The term “alkanoylamino” is used above for formula XVIII to mean —NHCOR⁷(R⁷ is alkyl or halo-substituted alkyl) including, but not limited to,formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino,trifluoroacetylamino and the like.

the term “alkylsulfonylamino” is used above for formula XVIII to mean“NHSO₂R⁸ (R⁸ is alkyl or halosubstituted alkyl) including, but notlimited to, methylsulfonylamino, ethylsulfonyl amino,trifluoromethylsulfonylamino and the like.

The term “N-alkyl-N-alkylsulfonylamino” is used above for formula XVIIIto mean —N(R⁹)SO₂R¹⁰ (R⁹ is alkyl and R¹⁰is alkyl or halosubstitutedalkyl) including, but not limited to, N-methyl-N-methylsulfonylamino,N-ethyl-N-methylsulfonylamino,N-n-propyl-N-methyl-sulfonylamino,N-isopropyl-N-methysufonylamino,N-methyl-N-trifluoromethyl-sulfonylamino,Nethyl-N-trifluoromethylsulfonylamino,N-n-propyl-N-trifluoromethyl-sulfonylamino andN-isopropyl-N-trifluoromethyl sulfonylamino.

The term “N-Wkyl-N-alkanoylamino” is used above for formula XVIII tomean —N(R¹¹)COR¹² (R¹¹ is alkyl and R¹² is alkyl or halosubstitutedalkyl) including, but not limited to, N-acetyl-N-methylamino,N-acetyl-Nethylamino, N-acetyl-N-n-propylamino,N-acetyl-N-isopropylamino, N-trifluoroacetyl-N-ethylamino,N-trifluoroacetyl-N-n-propylamino andN-trifluoroacetyl-N-isopropylamino.

Other more specific embodiments of this invention relate to the methodof treating cancer described immediately above, wherein the NK-1receptor antagonist that is administered is a compound as defined in anyof paragraphs (52)-(57) below, or a pharmaceutically acceptable salt ofsuch compound.

(52) A compound of the formula XVIII wherein Ar¹ and Ar² are eachphenyl.

(53) A compound as described in paragraph (52) wherein R² is methyl andR¹ is hydrogen.

(54) A compound as described in paragraph (53) wherein X is at the3-position of the quinuclidine ring and X is carboxy or aminocarbonyl.

(55) A compound as described in paragraph (54) wherein Y is saidalkenyl.

(56) A compound as described in paragraph (55) wherein Y is isopropenyl.

(57) A compound as described in paragraph (56) wherein Y ismethylsulfonyl, N-acetyl-N-methylamino orN-methyl-N-methylsulfonylamino.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein R is (C₁-C₆) alkyl;

X is (C₁-C₆) alkyl having one or more substituents bonded through aheteroatom;

Ar¹ and Ar² are each, independently, aryl optionally substituted by one(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) alkylthio, halogen, cyano, nitro,phenoxy, mono (C₁-C₆) alkylamino, di (C₁-C₆) alkylamino, halosubstituted(C₁-C₆) alkyl, or halosubstituted (C₁-C₆) alkoxy;

Y is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₃-C₈) cycloalkyl,Z—(CH₂)_(p)—, or W—(CH₂)_(m)—CHR²—(CH₂)_(n)—NR¹CO— wherein Y is at the4-, 5- or 6-position on the quinuclidine ring;

R¹ is hydrogen, (C₁-C₆) alkyl, benzyl or —(CH₂)_(r)—W;

R² is hydrogen or (C₁-C₆) alkyl which may be substituted by one hydroxy,amino, methylthio, mercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or—(CH₂)_(r)—W;

Z is (C₁-C₆) alkoxy, —CONR⁴R⁵, —CO₂R⁴, —CHR⁴OR⁵, —CHR⁴NR⁵R⁶, —COR⁴,—CONR⁴OR⁵ or optionally substituted aryl;

each W is, independently, cyano, hydroxymethyl, (C₂-C₆)alkoxymethyl,aminomethyl, mono-(C₁-C₆)alkylaminomethyl, di-(C₁-C₆) alkylaminomethyl,carboxyl, carbamoyl or (C₁-C₆) alkoxycarbonyl;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁-C₆) alkyl, (C¹-C₆) alkoxy,(C₃-C₈) cycloalkyl or an optionally substituted aryl or heterocyclicgroup;

p is 0 to 6; and

m, n and r are each, independently, 0 to 3;

or a pharmaceutically acceptable salt of such compound.

Other more specific embodiments of this invention relate to the methodof treating cancer described immediately above, wherein the NK-1receptor antagonist that is administered is a compound as defined in anyof paragraphs (58)-(60) below or a pharmaceutically acceptable salt ofsuch compound.

(58) A compound of the formula XIX wherein X is (C₁-C₆) alkyl having oneor two substituents selected from hydroxy, halogen, (C₁-C₆) alkoxy,(C²-C₆) alkanoyl, (C₂-C₆) alkanoyloxy, (C₁-C₆) alkylthio, mono (C₁-C₆)alkylamino, di-(C₁-C₆) alkylamino, amino, cyano and azido.

(59) A compound of the formula XIX as described in paragraph (58)wherein R is methyl and the OR group is at the 2-position; Ar¹ and Ar²are each phenyl, monochlorophenyl or monofluorophenyl; Y is hydrogen orZ—(CH₂)_(p)—, wherein Z is (C₁-C₆) alkoxy, —CONR⁴R⁵, —CO₂R⁴, —CHR⁴OR⁵,—CHR⁴NR⁵R⁶, —COR⁴ or —CONR⁴OR⁵; and Y is at the 5- or 6-position.

(60) A compound as described in paragraph (59) wherein X is (C₁-C₆)alkyl having one or two substituents selected from hydroxy, (C₁-C₆)alkoxy and (C₁-C₆) alkylthio; Ar¹ and Ar² are each phenyl; and Y ishydrogen or carboxy.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein X and Y are each, independently, hydrogen, halo, (C₁-C₆) alkyl,halosubstituted (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C⁶) alkylthio,(C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl or tri-(C₁-C₆) alkylsilyl;

Ar¹ and Ar² are each aryl optionally substituted by halo;

A is —CO— or —(CH₂)—;

Z—A— is at the 5 or 6 position on the quinuclidine ring;

Z is hydroxy, (C₁-C₆) alkoxy, NR¹R² or W¹—(CH₂)_(m)—CHR⁴—(CH²)_(n)—NR³wherein

R¹ and R², when taken separately, are each hydrogen or (C₁-C₆) alkyl;

R¹ and R², when taken together with the nitrogen atom to which they areattached, represent piperidino, pyrrolidino, morpholino, thiomorpholinoor piperazino;

R³ is hydrogen, (C₁-C₆) alkyl, benzyl or —(CH₂)_(r)—W²;

R⁴ is hydrogen or (C₁-C₆) alkyl which may be substituted by hydroxy,amino, methylthio, mercapto, benzyl, 4-hydroxylbenzyl, 3-indolylmethylor —(CH₂)_(s)—W³;

R³ and R⁴, when taken together, represent CH₂ or CH₂CH₂;

W¹, W² and W³ are each, independently, cyano, hydroxymethyl, (C₂-C₆)alkoxymethyl, aminomethyl, (C₁-C₆) alkylaminomethyl, [di(C₁-C₆)alkylamino]methyl, carboxyl, (C₁-C₆) alkylcarbamoyl,[di(C₁-C₆,)alkyl]carbamoyl, carbamoyl or [(C₁-C₆)alkoxy]carbonyl; and

m, n, r and s are each 0, 1, 2 or 3;

or a pharmaceutically acceptable salt of such compound.

As used above for formula XX, the term “alkylthio” means —S-alkyl,including but not limited to methylthio, ethylthio and the like.

As used above for formula XX, the term “alkylsulfinyl” means —SO-alkyl,including but not limited to methylsulfinyl, ethylsulfinyl,isopropylsulfinyl and the like.

As used above for formula XX, the term “alkylsulfonyl” means —SO₂-alkyl,including but not limited to methylsulfonyl, ethylsulfonyl,isopropylsulfonyl and the like.

As used above for formula XX, the term “aryl” means aromatic radicalsincluding but not limited to phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyland the like. These aryl groups can be substituted by (C₁-C₆) alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, halogen, cyano, nitro, phenoxy, mono-or di-(C₁-C₆) alkylamino and the like.

This invention also relates to a method of treating cancer in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of an NK-1 receptor antagonist that isa compound of the formula

wherein Y is (C₂-C₄) alkylene;

Z is a valence bond or (C₁-C₆) alkylene;

R¹ is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl,phenyl (C₁-C₆)alkyl or benzhydryl, wherein each of the ring moieties mayoptionally be substituted by one or more substituents independentlyselected from halogen, (C₁-C₆)alkyl, halosubstituted (C₁-C₆)alkyl,(C₁-C₆)alkoxy and halosubstituted (C₁-C₆)alkoxy;

R² is hydrogen or (C₁-C₆)alkyl;

R³ is hydrogen, hydroxy, cyano, amino or carboxy, provided that when Zis a valence bond, R³ must be hydrogen;

R⁴ represents a group of the formula (XXII) or (XXIII)

 wherein X¹, X² and X³ are each halo, hydrogen, nitro, (C₁-C₆)alkyl,halosubstituted (C₁-C₆) alkyl, (C₁-C₆)alkoxy, halosubstituted(C₁-C₆)alkoxy, hydroxy, amino, (C₁-C₆) alkylthio, (C₁-C₆)alkylsulfinylor (C₁-C₆)alkylsulfonyl;

Q¹ and Q² are each H₂, oxygen or sulfur;

A is valence bond, methylene, oxygen, sulfur or NH;

R5 and R” are each hydrogen or (C₁-C₆) alkyl; and

R⁷ is hydrogen, halogen, C₁-C₆ alkyl, halosubstituted C -C₆ alkyl orC₁-C₆ alkoxy;

or a pharmaceutically acceptable salt of such compound.

The term “halo”, as used above for formula XXI, includes chloro, fluoro,bromo and iodo.

The term “alkyl”, as used above for formula XXI, includes saturatedmonovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof.

The term “alkenyl”, as used above for formula XXI, refers to straight orbranched hydrocarbon chain radicals having one double bond including,but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1-and 2-butenyl.

The term “alkoxy”, as used above for formula XXI, refers to -O-alkyl,wherein alkyl is defined as above, and includes, but is not limited tomethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.

The term “alkylthio”, as used above for formula XXI, refers to —S-alkyl,wherein alkyl is defined as above, and includes, but is not limited tomethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isobutylthio, and t-butylthio.

The term “cycloalkyl”, as used above for formula XXI, unless otherwiseindicated, refers to cyclic hydrocarbon radicals including, but notlimited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “one or more substituents,” as used above for formula XXI,includes from one to the maximum number of substituents possible basedon the number of available bonding sites.

Compounds of the formulae I, X, XV, XVI, XVII, XVIII, XIX, XX and XXIcontain chiral centers and therefore exist in different enantiomericforms. The above definitions of these compounds include all opticalisomers and all stereoisomers of such compounds, and mixtures thereof.

Other more specific embodiments of this invention relate to any of theabove methods of treating cancer, wherein the NK-1 receptor antagonistthat is administered is selected from the group consisting of:

(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;

(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxyphenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)benzyl]amino-2-phenylpiperidine;

(2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)aminopiperidine;

(2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)aminopiperidine;

cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;

cis-3-(2-trifluoromethyibenzylamino)-2-phenylpiperidine;

cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(3methylphenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-thienyl)piperidine;

cis-3-(2-methoxybenzyiamino)-2-phenylazacycloheptane;

3-(2-methoxybenzylamino)4-methyl-2-phenylpiperidine;

3-(2-methoxybenzylamino)-5methyl-2-phenylpiperidine;

(2S,3S)-1-(5carboethoxypent-1-yl)-3-(2-methoxybenzylamino)-2phenylpiperidine;

(2S,3S)-1-(6hydroxyhex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(4-oxo4phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(5,6-dihydroxyhex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-[4-(4-4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;

cis-3-(2-methoxy-5-ethylbenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenylpiperidine;

(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methyl-carboxamidopent-1-yl)-2-phenylpiperidine;

(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzyl-amino)-2phenytpiperidine;

(2S,3S)-1-(5aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-3(2,5-dimethoxybenzylamino)-2-phenylpiperidine;

cis-3-(3,5-difluoro-2-methoxybenzyiamino)-2-phenylpiperidine;

cis-3-(4,5difluoro-2-methoxybenzylamino)-2-phenylpiperidine;

cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;

cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;

cis-1-(5,6-dihydroxyhex-1-yl)-(2,5imethoxybenzylamino)-2-phenylpiperidine;

cis-2-phenyl-3-[2-(prop-2-yloxy)benzylamino]piperidine;

cis-3-(2,5-dimethoxybenzyi)amino-2-(3-methoxyphenyl)piperidine;

cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxyphenyl)piperidine;

cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chlorophenyl)piperldine;

3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;

cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;

(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenylpiperidine;

2,4-dimethylthiazole-5sulfonic acid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]methylamide;

N-(4,5-dimethylthiazol-2-yl)-N-[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-yl-aminomethyl)phenyl]methanesulfonamide;

{5-[(4,5-dimethylthiazol-2-yl)methylamino]-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-yl)amine;

{5-(4,5dimethyfthiazol-2-ylamino)-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-ylamine;

4,5-dimethylthiazole-2-sulfonic acidmethyl-[3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)-4-trifluoromethoxyphenyl]-amide;

2,4-dimethylthiazole-5-sulfonic acid[4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;

2,4-dimethykthiazole-5-sulfonic acid[4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;

2,4dimethylthiazol-5-sulfonic acid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;

2,4-dimethylthiazole-5-sulfonic acid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide;

2,4-dimethyfthiazole-5-sulfonic acid[4isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide;

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo-[2.2.2]octan-3-amine;

(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-2-diphenylmethyl-3-(5-tert-butyl-2-methoxybenzyl)amino-1-azabicyclo[2.2.2]octane;

(2S,3S)-N-[5-(1-cyano-1-methylethyl)-2-methoxybenzyl]-2-phenylpiperidine-3-amine;

(2S,3S)-3-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl-2-phenylpiperidine-3-amine;

(2S,3S)-2-phenyl-N-[5-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-methoxybenzyl]piperidine-3-amine;

(2S,3S)-2-diphenylmethyl-N-[2-methoxy-5-(methylsulfonyl)benzyl]-1-azabicyclo[2.2.2]octane-3-amine;

(2S,3S)-2-diphenylmethyl-N-(5-isopropenyl-2-methoxybenzyl)-1-azabicyclo[2.2.2]octane-3-amine;

(2S,3S)-2-diphenylmethyl-N-[5-(1-hydroxy-1-mnethylethyl)-2-methoxybenzyl]-1-azabicyclo[2.2.2]octane-3-amine;

(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3carboxamide;

(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R, 4S, 5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo-[2.2.2]octane3-caboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3carboxylicacid;

(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane3-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-caboxylicacid;

(3R,4S,5S,6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-caboxylicacid;

(3R,4S,5S,6S)-5-(2-mothoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;

(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-caboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-caboxylicacid;

(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-caboxylicacid;

(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-caboxylic acid;

(3R,4S,6S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-cabcxylicacid; and

(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;

and the pharmaceutically acceptable salts of the foregoing compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formulae Ia, Ib, Ic, Id, Ie, X, XV, XVI, XVII,XVIII, XIX, XX and XXI may be prepared as described below. Unlessotherwise indicated, in the discussion that follows, structural formulaeIa, Ib, Ic, Id, Ie, X, XV, XVI, XVII, XVIII, XIX, XX and XXI and groupsII, III, IV, V, VI, VII, VIII, IX, XXII and XXIII are defined as above.

Compounds of the formula Ia and Ib may be prepared as described in U.S.Ser. No. 08/522,230, filed Oct. 7, 1993, corresponding to EP 675,886 andEP 806,423; which is a continuation-in-part of U.S. patent applicationSer. No. 988,653, which was filed on Dec. 10, 1992, now abandoned. Theseapplications are incorporated herein by reference in their entirety.

Compounds of the formula Ic may be prepared as described in U.S. Ser.No. 08/387,765, filed May 5, 1993, now U.S. Pat. No. 5,721,255corresponding to EP 655,996; which is a continuation-in-part of U.S.patent application Ser. No. 932,392, which was filed on Aug. 19, 1992,now abandoned, and PCT Patent Application PCT/US 93/09407, whichdesignates the United States and which was filed in the United StatesReceiving Office on Oct. 7, 1993 and published as WO 94/13663 on Jun.23, 1994. These applications and patents are incorporated herein byreference in their entirety.

Compounds of the formula Id may be prepared as described in U.S. Ser.No. 08/443,418, filed May 22, 1995, now U.S. Pat. No. 5,744,480; whichis a division of U.S. Ser. No. 08/167,881, filed May 5, 1992, now U.S.Pat. No. 5,773,450 corresponding to EP 589,924; which is acontinuation-in-part of U.S. Ser. No. 717,943, filed Jun. 20, 1991, nowabandoned; and in PCT Patent Application PCT/US 92/03571, whichdesignates the United States and which was filed in the United StatesReceiving Office on May 5, 1992 and published as WO 93/00331 on Jan. 7,1993. These applications and patents are incorporated herein byreference in its entirety.

Compounds of the formula Ie may be prepared as described in U.S. Ser.No. 08/615,257, filed Jul. 18, 1994, now U.S. Pat. No. 5,703,065corresponding to EP 719,266; which is a continuation of U.S. patentapplication No. 123,306, which was filed on Sep. 17, 1993, now abandonedand in PCT Patent Application PCT/IB 94/00221, which designates theUnited States and which was filed in the International Bureau on Jul.18, 1994 and was published as WO 95/07908 on Mar. 23, 1995. Theseapplications and patents are incorporated herein by reference in itsentirety.

When R³ is a group of the formula II, the starting materials of theformula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in U.S. Pat.No. 5,162,339, which issued on Nov. 11, 1992 and corresponds to EP409,931; in PCT Application PCT/US 88/04205 designating the UnitedStates, filed in the U.S. Receiving Office on Nov. 23, 1988 andpublished as WO 90/05525 on May 31, 1990; and in PCT Application PCT/US89/05338 designating the United States, filed in the U.S. ReceivingOffice on Nov. 20, 1989 and published as WO 90/105729 on May 31, 1990.This patent and these applications are incorporated herein by referencein their entirety.

When R³ is a group of the formula III, the starting materials of theformula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in U.S. Ser.No. 07/955,733, filed Apr. 25, 1991, now U.S. Pat. No 5,451,586corresponding to EP 532,527; which is a continuation-in-part of U.S.Ser. No. 532,525, filed Jun. 1, 1990, now abandoned; and in PCT PatentApplication PCT/US 91/02853, which designates the United States, wasfiled in the United States Receiving Office on Apr. 25, 1991 and waspublished as WO 91/18899 on Dec. 12, 1991. These applications andpatents are incorporated herein by reference in their entirety.

When R³ is a group of the formula IV, V or VI, the starting materials ofthe formula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in U.S. Ser.No. 08/403,967, filed Mar. 14, 1995, now U.S. Pat. No. 5,698,568 and inU.S. Ser. No. 08/403,987, filed Mar. 14, 1992, now U.S. Pat. No.5,641,786, both of which are divisions of U.S. Ser No. 07/1988,125,filed May 14, 1991, now U.S. Pat. No. 5,422,354; which is acontinuation-in-part of U.S. Ser. No. 557,442, filed Jul. 23, 1990, nowabandoned; PCT Patent Application PCT/US 91/03369, which designates theUnited States, was filed in the United States Receiving Office on May14, 1991 and was published as WO 92/01688 on Feb. 6, 1992. Theseapplications and patents are incorporated herein by reference in theirentirety.

When R³ is a group of the formula VII, the starting materials of theformula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in U.S. Ser.No. 08/014,970, filed Feb. 8, 1993, now U.S. Pat. No. 5,332,817, whichis a division of U.S. Ser. No. 724,268, filed Jul. 1, 1991, now U.S.Pat. No. 5,232,929 corresponding to EP 594,636; which is acontinuation-in-part of U.S. Ser. No. 619,361, filed Nov. 28, 1990, nowabandoned; in PCT Application PCT/US 90/00116 designating the UnitedStates, filed in the U.S. Receiving Office on Jan. 4, 1990 and publishedas WO 91/09344 on Jul. 11, 1991; and in PCT Application PCT/US 92104008designating the United States, filed in the U.S. Receiving Office on May21, 1992 and published as WO 93/01170 on Jan. 21, 1993; U.S. Ser. No.08/273,662, filed Jul. 12, 1994, now U.S. Pat. No. 5,663,349; which is acontinuation of U.S. Ser. No. 07/800,667, filed Nov. 27, 1991, now U.S.Pat. No. 5,364,943; which is a continuation-in-part of U.S. Ser. No.531,265, filed May 31, 1990, now abandoned; in PCT Patent ApplicationPCT/US 91/02541, which designates the United States, was filed in theUnited States Receiving Office on Apr. 12, 1991 and was published as WO91/18878 on Dec. 12, 1991 corresponding to EP 532,515; in PCTApplication PCT/US 92/09929 designating the United States, filed in theU.S. Receiving Office on Nov. 24, 1992 and published as WO 93/11110 onJun. 10, 1993; and in U.S. Ser. No. 08/119,149, filed Jan. 14, 1992, nowU.S. Pat. No. 5,686,615; which is a continuation of U.S. Ser. No.675,244, filed Mar. 26, 1991, now abandoned; and PCT Patent ApplicationPCT/US 92/00065, which designates the United States, was filed in theUnited States Receiving Office on Jan. 14,1992 and was published as WO92/17449 on Oct. 15,1992. These applications and patents areincorporated herein by reference in their entirety.

When R³ is a group of the formula VIII, the starting materials of theformula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in PCTPatent Application PCT/US 91/05776, which designates the United States,was filed in the United States Receiving Office on Aug. 20, 1991 and waspublished as WO 92/06079 on Apr. 16, 1992 above-mentioned U.S. Ser. No.08/273,662 and applications related thereto; and above-mentioned PCT/US92/00065 and applications related thereto. These applications andpatents are incorporated herein by reference in their entirety.

When R³ is a group of the formula IX, the starting materials of theformula NH₂R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic, Id and Ie may be prepared as described in U.S. Ser.No. 08/167,851, filed Jun. 11, 1992, now U.S. Pat. No. 5,604,252corresponding to EP 591,333; which is a continuation-in-part of U.S. SerNo. 719,884, filed Jun. 21, 1991, now abandoned; and in PCT PatentApplication PCT/US 92/04697, which designates the United States andwhich was filed in the United States Receiving Office on Jun. 11, 1992and published as WO 93/00330 on Jan. 7, 1993. These applications andpatents are incorporated herein by reference in their entirety.

Compounds of the formula X may be prepared as described in U.S. Ser. No.08/175,353, filed May 18, 1992, now U.S. Pat. No. 5,716,965corresponding to EP 585,328; and in PCT Patent Application PCT/US92/04002, which designates the United States, was filed in the UnitedStates Receiving Office on May 19, 1992 and was published as WO 92/20676on Nov. 26, 1992. This application is incorporated herein by referencein its entirety.

Compounds of the formula XV may be prepared by the procedure describedin PCT Patent Application PCT/US 92/04002, which designates the UnitedStates, was filed on May 19, 1992 and published as WO 92/20676 on Nov.26, 1992. This application is incorporated herein by reference in itsentirety.

Compounds of the formula XVI may be prepared as described in U.S. Ser.No. 08/513,798, filed Dec. 10, 1993, now U.S. Pat. No. 5,688,806corresponding to EP 687,268; which is a continuation-in-part of U.S.Ser. No. 026,382, filed Mar. 4, 1993, now abandoned; and in PCT PatentApplication PCT/US 93/11793, which designates the United States, andwhich was filed on Dec. 10, 1993 in the U.S. Receiving Office andpublished as WO 94/20500 on Sep. 15, 1994. These applications andpatents are incorporated herein by reference in their entirety.

Compounds of the formula XVII may be prepared as described in U.S. Ser.No. 08/428,240, filed Sept. 30, 1993, corresponding to EP 665,843; andin PCT Patent Application PCT/US 93/09169, which designates the UnitedStates and which was filed in the U.S. Receiving Office on Sep. 30, 1993and published as WO 94/10170 on May 11, 1994. These applications areincorporated herein by reference in their entirety.

Compounds of the formula XVIII may be prepared as described in U.S. Ser.No. 08/416,913, filed Sep. 30, 1993, now U.S. Pat. No. 5,604,241corresponding to EP 665,844; and in PCT Patent Application PCT/US93/09168, which designates the United States and which was filed in theU.S. Receiving Office on Sep. 30, 1993 and published as WO 94/08997 onApr. 28, 1994. These applications are incorporated herein by referencein their entirety.

Compounds of the formula XIX may be prepared as described in U.S. Ser.No. 08/556,916, filed May 13, 1994, now U.S. Pat. No. 5,741,797corresponding to EP 699,199; and in PCT Patent Application PCT/JP94/00781, which designates the United States and which was filed in theJapanese Receiving Office on May 13, 1994. This application isincorporated herein by reference in its entirety.

Compounds of the formula XX may be prepared as described in U.S. Ser.No. 08/637,682, filed Jul. 5, 1994; and in PCT Patent Application PCT/JP94/01092, which designates the United States and was filed in theJapanese Receiving Office on Jul. 5, 1994. These applications areincorporated herein by reference in their entirety.

Compounds of the formula XXI may be prepared as described in U.S. Ser.No. 08/957,176, filed Oct. 24, 1997, which is a continuation of U.S.Ser. No. 08/617,896, filed Sep. 13, 1994, corresponding to EP 719,253,now abandoned; and in PCT Patent Application PCT/JP 94/01514, whichdesignates the United States and was filed in the Japanese ReceivingOffice on Sep. 13, 1994. These applications are incorporated herein byreference in their entirety.

The therapeutic agents that are basic in nature are capable of forming awide variety of different salts with various inorganic and organicacids. Examples of acids that form suitable pharmaceutically acceptablesalts for use in this invention are those that form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a therapeutic agent from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basetherapeutic agents of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained.

Those therapeutic agents of this invention that are also acidic innature are capable of forming base salts with various pharmacologicallyacceptable cations. The chemical bases that are used as reagents toprepare the pharmaceutically acceptable base salts of the therapeuticagents are those that form non-toxic base salts with the acidictherapeutic agents. Such non-toxic base salts include those derived fromsuch pharmacologically acceptable cations as sodium, potassium, calciumand magnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

The following references refer, collectively, to quinuclidine,piperidine, ethylene diamine, pyrrolidine and azanorbornane derivativesand related compounds that exhibit activity as substance P receptorantagonists and can therefore be employed in the methods of thisinvention, and to methods of preparing the same: U.S. Pat. No.5,162,339, which issued on Nov. 11, 1992; U.S. Pat. No. 5,232,929, whichissued on Aug. 3, 1993; World Patent Application WO 92/20676, publishedNov. 26, 1992; World Patent Application WO 93/00331, published Jan. 7,1993; World Patent Application WO 92/21677, published Dec. 10, 1992;World Patent Application WO 93/00330, published Jan. 7, 1993; WorldPatent Application WO 93/06099, published Apr. 1, 1993; World PatentApplication WO 93/10073, published May 27, 1993; World PatentApplication WO 92/06079, published Apr. 16, 1992; World PatentApplication WO 92/12151, published Jul. 23, 1992; World PatentApplication WO 92/15585, published Sep. 17, 1992; World PatentApplication WO 93/10073, published May 27, 1993; World PatentApplication WO 93/19064, published Sep. 30, 1993; World PatentApplication WO 94/08997, published Apr. 28, 1994; World PatentApplication WO 94/04496, published Mar. 3, 1994; World PatentApplication WO 94/13663, published Jun. 23, 1994; World PatentApplication WO 94/20500, published Sep. 15, 1994; World PatentApplication PCT/IB94/00221, which designates the United States and wasfiled on Jul. 18, 1994; World Patent Application PCT/JP94/00781, whichdesignates the United States and was filed on May 13, 1994; World PatentApplication PCT/JP94/01092, which designates the United States and wasfiled on Jul. 5, 1994; and World Patent Application PCT/JP94/01514,which designates the United States and was filed on Sep. 13, 1994. Allof the foregoing World Patent Applications designate the United States.The foregoing patents and patent applications are incorporated herein byreference in their entirety.

The specific NK-1 receptor antagonists listed in the Summary of theInvention can be prepared by methods described in the published patentsand patent applications listed above, as well as in the scientificliterature.

Other NK-1 receptor antagonists that can be employed in the methods ofthis invention are those compounds and pharmaceutically acceptable saltsdescribed in the following references: European Patent Application EP499,313, published Aug. 19, 1992; European Patent Application EP520,555, published Dec. 30, 1992; European Patent Application EP522,808, published Jan. 13, 1993, European Patent Application EP528,495, published Feb. 24, 1993, PCT Patent Application WO 93/14084,published Jul. 22, 1993, PCT Patent Application WO 93/01169, publishedJan. 21, 1993, PCT Patent Application WO 93/01165, published Jan. 21,1993, PCT Patent Application WO 93/01159, published Jan. 21, 1993, PCTPatent Application WO 92/20661, published Nov. 26, 1992, European PatentApplication EP 517,589, published Dec. 12, 1992, European PatentApplication EP 428,434, published May 22, 1991, European PatentApplication EP 360,390, published Mar. 28, 1990, PCT Patent ApplicationWO 95/19344, published Jul. 20, 1995, PCT Patent Application WO95/23810, published Sep. 8, 1995, PCT Patent Application WO 95/20575,published Aug. 3, 1995 and PCT Patent Application WO 95/28418, publishedOct. 26, 1995.

Generally, in carrying out the methods of this invention, the NK-1receptor antagonist will be administered to an adult human in an amountranging from about 0.07 to about 21 mg per kg body weight of the subjectbeing treated per day, in single or divided doses, preferably from about0.36 to about 4.3 mg/kg. Variations may nevertheless occur dependingupon the species of the subject being treated and its individualresponse to said medicament, as well as on the type of pharmaceuticalformulation chosen and the time period and interval at which suchadministration is carried out. In some instances, dosage levels belowthe lower limit of the aforesaid range may be more than adequate, whilein other cases still larger doses may be employed without causing anyharmful side effect, provided that such larger doses are first dividedinto several small doses for administration throughout the day.

The NK-1 receptor antagonists and their pharmaceutically acceptablesalts that are employed in the methods of this invention are hereinafteralso referred to as the “therapeutic agents”. The therapeutic agents canbe administered via either the oral or parenteral route.

The therapeutic agents may be administered alone or in combination withpharmaceutically acceptable carriers or diluents by either of the routespreviously indicated, and such administration may be carried out insingle or multiple doses. More particularly, the novel therapeuticagents of this invention can be administered in a wide variety ofdifferent dosage forms, i.e., they may be combined with variouspharmaceutically acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, suppositories, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non4toxic organic solvents, etc. Moreover, oral pharmaceuticalcompositions can be suitably sweetened and/or flavored. In general, thetherapeutic compounds of this invention are present in such dosage formsat concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a therapeutic agent ineither sesame or peanut oil or in aqueous propylene glycol may beemployed. The aqueous solutions should be suitably buffered if necessaryand the liquid diluent first rendered isotonic. These aqueous solutionsare suitable for intravenous injection purposes. The oily solutions aresuitable for intraarticular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell known to those skilled in the art.

The activity of certain therapeutic agents as substance P receptorantagonists may be determined by their ability to inhibit the binding ofsubstance P at its receptor sites in bovine caudate tissue, employingradioactive ligands to visualize the tachykinin receptors by means ofautoradiography. The substance P antagonizing activity of the hereindescribed compounds may be evaluated by using the standard assayprocedure described by M. A. Cascieri et al., as reported in the Journalof Biological Chemistry, Vol. 258, p. 5158 (1983). This methodessentially involves determining the concentration of the individualcompound required to reduce by 50% the amount of radiolabelled substanceP ligands at their receptor sites in said isolated cow tissues, therebyaffording characteristic IC₅₀ values for each compound tested.

In this procedure, bovine caudate tissue is removed from a −70° C.freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris(i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol)hydrochloride buffer having a pH of 7.7. The homogenate is centrifugedat 30,000×G for a period of 20 minutes. The pellet is resuspended in 50volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000×Gfor another twenty-minute period. The pellet is then resuspended in 40volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM ofcalcium chloride, 2 mM of magnesium chloride, 4 μg/ml of bacitracin, 4μg/ml of leupeptin, 2 μg of chymostatin and 200 μg/ml of bovine serumalbumin. This step completes the production of the tissue preparation.

The radioligand binding procedure is then carried out in the followingmanner, viz., by initiating the reaction via the addition of 100 μl ofthe test compound made up to a concentration of 1 μM, followed by theaddition of 100 μl of radioactive ligand made up to a finalconcentration 0.5 mM and then finally by the addition of 800 μl of thetissue preparation produced as described above. The final volume is thus1.0 ml, and the reaction mixture is next vortexed and incubated at roomtemperature (ca. 20° C.) for a period of 20 minutes. The tubes are thenfiltered using a cell harvester, and the glass fiber filters (WhatmanGF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with thefilters having previously been presoaked for a period of two hours priorto the filtering procedure. Radioactivity is then determined in a Betacounter at 53% counting efficiency, and the IC₅₀ values are calculatedby using standard statistical methods.

The ability of the NK-1 receptor antagonists used in the methods of thisinvention to inhibit the proliferation of small cell lung carcinomacells can be determined using the in vivo and in vitro cellproliferation assays described by Orosz et al., International Journal ofCancer, 1995, 60, 82-87, and by Bunn et al., Cancer Research, 1994, 54,3602-3610.

What is claimed is:
 1. A method of treating small cell lung carcinoma,extra pulmonary small cell carcinoma or a neuroendocrine tumor in amammal in need of such treatment, comprising administering to saidmammal a therapeutically effective amount of an NK-1 receptor antagonistselected from the group consisting of 2,4-dimethylthiazole-5-sulfonicacid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]methylamide;N-(4,5-dimethylthiazol-2-yl)-N-[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-yl-aminomethyl)phenyl]methanesulfonamide;{5-[(4,5-dimethylthiazol-2-yl)methylamino]2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-yl)amine;{5-(4,5-dimethylthiazol-2-ylamino)-2-methoxybenzyl}-((2S,3S)-2-phenylpiperidin-3-ylamine;4,5-dimethylthiazole-2-sulfonic acidmethyl-[3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)-4-trifluoromethoxyphenyl]amide;2,4-dimethylthiazole-5-sulfonic acid[4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]methylamide;2,4-dimethylthiazole-5-sulfonic acid[4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]isopropylamide;2,4-dimethylthiazole-5-sulfonic acid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]isopropylamide;2,4-dimethylthiazole-5-sulfonic acid[4-methoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]isobutylamide;2,4-dimethylthiaxole-5-sulfonic acid[4-isopropoxy-3-((2S,3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]isobutylamide;and the pharmaceutically acceptable salts of the foregoing compounds.